36 th Annual ASQ-FDC/FDA Conference June 23, 2005

1. CHPA Guidelines on Stability Testing of OTC Monograph Drug Products Karen L. Lucas Patricia Werschulz Pfizer Consumer Healthcare BMS Worldwide Consumer 36th Annual ASQ-FDC/FDA Conference June 23, 2005 ASQ-FDA 6-23-05 CHPA Stability Working Group

2. Overview • Background • Who and What is the CHPA Stability Working Group (SWG)? • What are we trying to fix in the OTC World? • Risks vs. Benefits of Having a Guideline • Where are we today & What’s next? ASQ-FDA 6-23-05 CHPA Stability Working Group

3. Background • In August 2002, CHPA was approached by a member company to obtain support in addressing FDA’s lack of guidance on stability testing requirements for OTC Monograph Drug Products. • As a starting point toward further dialogue with both the agency and industry, the development of a draft stability guideline document was proposed. • In May 2003, CHPA granted approval to form the Stability Working Group (SWG). ASQ-FDA 6-23-05 CHPA Stability Working Group

4. Stability Working Group Members • Karen L. Lucas, Pfizer Consumer Healthcare - Chairperson • Patricia Werschulz, Bristol-Myers Squibb • Jeffrey Needels, Novartis Consumer Health • David Wiggins, Schering Plough • Judy Lee, Purdue Pharma • Bruce Henning, Bayer Healthcare Consumer Care • Jane Cai, Johnson & Johnson Consumer • Eleanor Freeman, McNeil Consumer • Mary W. Seibel, Procter & Gamble Health Care • Tony Psihoules, Colgate-Palmolive • Bill Van Meter, Perrigo • Frederick Razzaghi, CHPA - Facilitator ASQ-FDA 6-23-05 CHPA Stability Working Group

5. A Need was Identified……..SWG’s Goal Prior to this CHPA guideline, the non-prescription industry did not have directly applicable stability testing guidance for OTC monograph drug products not regulated by an NDA/ANDA. Historically, non-prescription drug companies developed their stability testing programs based upon their best interpretation and practical application of the most current FDA guidance for new drug products. ASQ-FDA 6-23-05 CHPA Stability Working Group

6. A Need was Identified……SWG’s Goal (cont’d) • Because of the unique requirements associated with new OTC drug products, the direct application of the FDA guidance is frequently inappropriate and impractical. Drug products with an OTC monograph will typically be well characterized with a: • significant body of information • well known safety profile • long history of use in multiple dosage forms. • For this reason, the OTC Industry (under the CHPA) is proposing this guideline for non-prescription (OTC) drug products not regulated by an NDA/ANDA. ASQ-FDA 6-23-05 CHPA Stability Working Group

7. A Need was Identified…….SWG’s Goal (cont’d) • SWG’s Goal: • To create an OTC Stability Guideline in order to establish science-based best practices and minimum requirements for the development and launch of OTC Monograph Drug Products in the U.S. (that are not regulated by an NDA/ANDA). ASQ-FDA 6-23-05 CHPA Stability Working Group

8. We Recognized The Problem….. • Rx World (NCEs): • ICH Q1A and FDA (3 batches, LT & ACC, 12 months data) • Generic World (NCEs with experience): • 1987 and draft 1998 FDA Stability Guidelines • OTCs (extensive experience, good safety record, Monograph Drugs): • The existing FDA stability references applicable to OTC monograph products (e.g.. the Joel Davis "Dating Game" memo from 1978, and FDA Inspector Technical Guide ITG-41 from 1985) are somewhat dated. Something more recent is preferable in order to justify the OTC Industry's approach to stability testing. • Current practice is for companies to use ICH Q1A. Q1A is the most recent guidance that has been developed. It represents the most conservative set of stability requirements. Clearly, OTCs do not require as much testing, and in practice, companies are not strictly following ICH. Bottom Line: The NCE requirements are excessive! ASQ-FDA 6-23-05 CHPA Stability Working Group

9. What are we trying to fix??? • We recognize that there are a number of Warning Letters & Recalls for inadequate and/or no established Stability Programs within OTC Companies. • This guidance will help CHPA Member Companies develop adequate Stability Programs and reach a “higher state” of compliance. ASQ-FDA 6-23-05 CHPA Stability Working Group

10. Warning Letters & Recalls (1997 – 2003) • Warning Letters to OTC Companies: • Failure to establish a written Stability Program – 33 • Failure to follow written Stability Program – 19 • No data available to support labeled expiration -11 • Inadequate Stability Program - 10 • Methods not stability indicating - 3 • Recalls by OTC Companies: • Data does not support labeled expiration – 6 • Failed dissolution – 5 • Sub-potency (stability failure) – 4 • Other stability failure – 3 • Non-uniformity in potency results – 1 • Degradation failure - 1 ASQ-FDA 6-23-05 CHPA Stability Working Group

11. Risks to Industry(Having a Guidance) • We may provide a starting point for FDA to use to over-regulate the OTC Industry. • May decrease flexibility of some individual CHPA Member Companies not already meeting minimum standards. • Uncertainty about Industry acceptance. • This would only be ONE part of FDA’s “Quality System”. ASQ-FDA 6-23-05 CHPA Stability Working Group

12. Benefits to Industry (Having a Guidance) • Helps us to minimize the Regulatory Burden: • lower the Regulatory Risk through science – use our knowledge and experience to base decisions! • Reduces risk especially for CHPA member-companies that do not have an established Stability Program! • Self-regulation works to advantage of Government, Industry & Consumer! • Helps to avoid / minimize Over-Regulation. • In alignment with FDA’s cGMPs for the 21st Century Initiative: A Risk-Based Approach! • Science-based Risk Management: we can use science & knowledge to base decisions. • Creates a “Level Playing Field” for everyone. ASQ-FDA 6-23-05 CHPA Stability Working Group

13. Benefits to Industry (Having a Guidance)….cont’d • Gives us the opportunity to reduce the amount of stability testing required prior to launch in the US. • Reduce “Time-to-Market”/ Satisfies a Business Need: • Allows business units to plan better (Increase Efficiency). • Provides companies a “fast-track” option for development of OTCs. • Allows flexibility to reduce or eliminate testing under specific circumstances. • Allows flexibility to use smaller scale batches. • Creates an “Identity” for the uniqueness of the OTC Industry. • Every company is essentially at risk because ICH Q1A does NOT apply to OTCs! ASQ-FDA 6-23-05 CHPA Stability Working Group

14. Our “Targeted State” (What we would like to see): • Clear stability requirements. • Elimination of Non-Value Added (NVA) activities. • Demystify stability requirements for non-technical people. • Ability to plan more accurately & reliably. • Leverage to simplify our complex / inefficient approach. • Zero adverse impact on “time-to-market”. • Science-based Risk Management! Bottom Line: • “Allow science to run our Stability Programs”. OTCs have more experience, history, safety. ASQ-FDA 6-23-05 CHPA Stability Working Group

15. How Did We Get To… Where We Are Today? • A Voluntary Alternative Method for doing OTC Monograph Drug Product Stability was posted on the CHPA Website for Industry comments through June 18, 2004. • We had asked CHPA member-companies to look at their internal procedures and comment where the discrepancies were against the proposed guideline. • 6 CHPA member-companies responded with feedback / comments. • Published as a a CHPA Voluntary Guideline (along with Industry comments)as of 10/8/04. ASQ-FDA 6-23-05 CHPA Stability Working Group

16. Objectives of the Guideline • To define the minimum stability data package to support the commercial distribution of OTC monograph drug products in the United States per climatic zone II. The stability data package will be based on development stability studies. These studies will be used to establish the tentative expiration dating period and label storage statement for the OTC monograph drug product. ASQ-FDA 6-23-05 CHPA Stability Working Group

17. Objectives of the Guideline • This guideline recognizes that a significant body of scientific information may exist for OTC drug products. Alternative approaches may be used when they are scientifically justified. ASQ-FDA 6-23-05 CHPA Stability Working Group

18. Scope of the Guideline • This guideline applies specifically to OTC monograph drug product stability. • This guideline does not currently seek to cover the stability testing of: • Non-prescription drug products regulated by an NDA/ANDA • Drug substances • Drug products used in clinical trials • Marketed product stability ASQ-FDA 6-23-05 CHPA Stability Working Group

19. Scope of the Guideline • Additionally, this guideline is not applicable to: • Specific details of the sampling and testing for particular dosage forms in their proposed container closures • Safety studies ASQ-FDA 6-23-05 CHPA Stability Working Group

20. Details of the Guideline • SELECTION OF BATCHES • Data should be available on at least one primary batch of the drug product. Additional primary batches may be necessary for new product formulations and instances where no similar formulations exist. • Same formulation / same container closure system as proposed for marketing. • Manufacturing process should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. • Batch(es) should be at least pilot scale (1/10 Production Scale); a scientific rationale may be used to justify a smaller batch size. ASQ-FDA 6-23-05 CHPA Stability Working Group

21. Details of the Guideline • TESTING FREQUENCY • The frequency of testing should be designed in order to adequately determine the stability profile for the drug product - typically 0, 3, 6, 12, and 24 months, and annually thereafter through the proposed shelf-life. Other time points (such as 9, 18, 30 months) may also be appropriate. • When the drug product fails to meet the established shelf-life criteria at the accelerated storage condition (such as 40C/75%RH), alternative accelerated conditions may be used to insure that at minimum, some acceptable accelerated data is available to show that the product can withstand the typical excursions experienced in the distribution chain once the product is marketed. ASQ-FDA 6-23-05 CHPA Stability Working Group

22. Details of the Guideline (cont’d) • STORAGE CONDITIONS • GENERAL CASE: • Long Term 25 ± 2°C / 60 ± 5% RH • Accelerated 40 ± 2°C / 75 ± 5% RH • DRUG PRODUCTS PACKAGED IN SEMI-PERMEABLE CONTAINERS: • Long Term 25 ± 2°C / 40 ± 5% RH • Accelerated 40 ± 2°C / NMT 25% ± 5% RH ASQ-FDA 6-23-05 CHPA Stability Working Group

23. Details of the Guideline (cont’d) • EVALUATION OF STABILITY DATA: • A scientific approach should be adopted in the presentation and evaluation of stability information for establishing a tentative expiry period. The scientific assessment should include the results from physical, chemical and microbiological data on the dosage form as well as a “body of knowledge” which may consist of: • Results from research and development batches on similar or closely related formulations. • Results from research and development batches on similar or closely related marketed products. • Data published in the literature, as well as results from the specific stability study. ASQ-FDA 6-23-05 CHPA Stability Working Group

24. Details of the Guideline (cont’d) • EVALUATION OF STABILITY DATA: • When the data from an accelerated stability study remains within established limits, while maintaining potency, a tentative expiry period can be assigned prior to marketing the product. • A 24-month expiry period may be assigned upon successful completion of three months accelerated testing. ASQ-FDA 6-23-05 CHPA Stability Working Group

25. Details of the Guideline (cont’d) • EVALUATION OF STABILITY DATA: • Using sound scientific judgment, shorter expiry periods may be assigned based on less than three months of accelerated testing and longer tentative expiry periods may be justified using extended periods of accelerated testing. • Any longer tentative expiry period or extension of an expiration dating period should be made based on the previous histories of similar products, sound scientific judgment, calculations using the Arrhenius equation, all with appropriate documentation. ASQ-FDA 6-23-05 CHPA Stability Working Group

26. Why Follow this Alternative Approach? • The OTC Industry plays a role in the overall healthcare of the nation. This Guideline would help us create an identity for the uniqueness of the OTC Industry. Alternatives to adopting a “Voluntary Standard” would include following the cumbersome ICH stability requirements or wait for the FDA to develop such a Guideline on this topic. • We all participate in this business and benefit from it, therefore we all should at least have a minimum standard to continue to put quality OTC products on the market for consumers. ASQ-FDA 6-23-05 CHPA Stability Working Group

27. Where We Would Like to Go From Here? • Continue to engage in or share our information with the Industry via conferences, meetings, etc. • Phase II – The Stability Working Group has commenced activities to update the Guideline to include changes to marketed OTC Monograph Drug Products. • Revisit the Guideline at the CHPA Executive Level if FDA endorsement is ever sought. ASQ-FDA 6-23-05 CHPA Stability Working Group

28. Thank You For Attending! ASQ-FDA 6-23-05 CHPA Stability Working Group